Project Summary Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized pathologically by the degeneration of dopaminergic neurons in the substantia nigra. Mitochondria! dysfunction and resulting oxidative stress have been implicated in PD pathogenesis because exposure to environmental mitochondrial toxins leads to PD-like pathology. Recently, several genes mediating familial forms of PD have been identified. The study of these genes is providing valuable insights into the mechanisms that lead to dopaminergic neuronal degeneration. dardarin (dar), the most recently identified PD gene, encodes a large protein belonging to a novel protein family with Ras/GTPase and kinase domains. The functions of dar are unknown and no in vivo studies have been reported, however in vitro evidence suggests that Dar localizes to mitochondria. To identify the cellular processes in which dar functions, phenotypes resulting from loss-of-function and overexpression of dar in Drosophila will be analyzed, with an emphasis on mitochondrial function. Additionally, the molecular nature of the PD-causing mutations in human dar will be explored by generating the analogous mutations in the Drosophila homolog, and analyzing phenotypes that result from the expression of these pathogenic alleles. Finally, dopaminergic neurons will be examined to determine whether dar loss-of-function, overexpression, or expression of disease alleles specifically sensitizes these neurons to degeneration and/or mitochondrial defects. This work will provide insight into the cellular processes in which dar functions, and the mechanisms by which pathogenic mutations in dar result in dopaminergic neuronal degeneration. By adding to our growing understanding of PD pathogenesis, these studies will move us closer to a definitive treatment for this devastating disease. Relevance Parkinson's Disease (PD) is a devastating neurodegenerative movement disorder that affects 1% of people over the age of 60. By studying how genetic mutations cause PD, we can better understand the mechanisms leading to this disease. This knowledge will aid in the development of more effective treatments, preventions, and diagnostic tools.